Lipase





Lipase is a subclass of esterases which catalyzes the hydrolysis of ester bonds in lipid substrates and is essential for fat digestion. It is primarily produced in the pancreas, but can be found in the mouth and stomach as well. The lipase typically digests fat lipids into monoglycerides and free fatty acids, with the resulting monomers subsequently shuttled to the small intestine and eventually absorbed into the lymphatic system.

Lipase Catalytic Mechanism
Although a diverse array of lipase enzymes are found in nature, occupying diverse protein scaffolds, most are built upon an alpha/beta hydrolase fold  and possess a chymotrypsin-like catalytic triad comprised of an acidic residue, a histidine, and a serine nucleophile. In the case of the images above of a horse pancreatic lipase, the catalytic triad is comprised of Ser 152, Asp 176 and His 263. This catalytic triad functions like most found in nature, first with the Aspartic acid forming a hydrogen bond with His 263, increasing the pKa of the histidine imidazole nitrogen. This allows the Histidine to act as a powerful general base and deprotonate the serine. The deprotonated serine then can serve as a nucleophile and attack the glycerol backbone of the lipid substrate. A water molecule then donates a proton to the histidine, creating a reactive hydroxyl anion, which can attack the carbonyl carbon of the lipid, releasing the catalytic serine and creating monoglyceride and fatty acid monomers that diffuse away.

3D Structures of Lipase
Update June 2011

Eukaryote natives:
1hpl – hLip – horse

1hlg – hLip – human - gastric

3jw8, 3hju – mono-glyceride hLip

1jmy – hBSSL

1akn – cBSSL – cattle

2bce - cBSSL (mutant)

1f6w - cBSSL – catalytic domain

3o0d – Lip – Yarrowia lipolytica

Prokaryote natives:
3guu, 1lbs, 1lbt, 1tca, 1tcb, 1tcc – CaLipA – Candida antarctica

2veo – CaLipA – closed state

3icv – CaLipB (mutant)

1gz7, 1lpm, 1lps– CrLip 2 – Candida rugosa - closed state

1crl, 1trh – CrLip – open state

1llf – Lip – Candida cylindracea

3g7n – Lip - Penicillium expansum

1tia - Lip – Penicillium camemberti

2qua, 2qub – LipA – Serratia marcescens

2hih – Lip – Staphylococcus hyicus

2fx5 – Lip – Pseudomonas mendocina

1yzf – Lip – Enterococcus faecalis

1dt3, 1dt5, 1dte, 1du4, 1ein, 1tib – TlLip - Thermomyces lanuginose

1jfr – Lip – Streptomyces exfoliates

1oil – BcLip - Burkholderia cepacia

2lip – BcLip – open state

1cvl – Lip – Chromobacterium viscosum

1lgy – Lip II – Rhizopus niveus

1tic - Lip – Rhizopus oryzae

1thg – Lip – Geotrichum candidum

3tgl, 4tgl, 1tgl – RmLip– Rhyzomucor miehei

2zvd – PsLip - Pseudomonas sp. – open state

2z8x - PsLip – extracellular

2zj6, 2zj7 – PsLip (mutant)

2z8z – PsLip(mutant) – closed state

3lip, 3a6z - Lip - Pseudomonas cepacia – open state

1qge, 1tah – Lip – Pseudomonas glumae

2w22 – Lip – Geobacillus thermocatenulatus

1ji3, 1ku0 – Lip – Bacillus stearothermophilus

1ah7 - Lip – Bacillus cereus

2qxt, 2qxu, 1isp, 1i6w - BsLip – Bacillus subtilis

3d2a, 3d2b, 3d2c, 1t2n, 1t4m - BsLip (mutant)

2ory – Lip – Photobacterium lypoliticum

2z5g, 2dsn – Lip T1 – Geobacillus zalihae

3p94 – Lip – Parabacteroides distasonis

3ngm – Lip – Gibberella zeae

Lipase/colipase complexes. The colipase is a co-enzyme whose binding to lipase optimizes the enzymatic activity
1n8s – hLip+colipase II

1eth, 1lpa - Lip+colipase II - pig

Hormone-sensitive-lipases (LIPE) hydrolyze the first fatty acid of the triacylglycerol substrate
3k6k – EstE7(LIPE) – metagenome library

3fak, 3dnm – EstE5(LIPE) – metagenome library

1evq – AaEst2(LIPE) – Alicyclobacillus acidocaldarius

1u4n – AaEst2(LIPE) (mutant)

Putative lipases; Proteins with unknown function but structural similarity to lipase obtained in structural genomics projects.
2rau - Lip – Sulfolobus solfataricus

3bxp, 3d3n - Lip – Lactobacillus plantarum

3e0x - Lip – Clostridium acetobutylicum

1z8h – Lip – Nostoc sp. PCC 712

1vj3 - Lip – Nostoc sp.

3bzw – Lip - Bacteroides thetaiotaomicron

2pbl – Lip - Silicibacter

Lipase + inhibitors
3jwe, 3pe6 - mono-glyceride hLip + SAR629 – covalent inhibitor

3l1h – EstE5(LIPE)+FeCl3 – noninvasive inhibitor

3l1i, 3l1j - EstE5(LIPE)+CuSO4 – noninvasive inhibitor

3lij - EstE5(LIPE)+ZnSO4– noninvasive inhibitor

3h18, 3h17 - EstE5 (LIPE)+PMSF

3h19, 3h1b, 3h1a – EstE5 (LIPE)+methyl alcohol

3h1a – EstE5 SLIPE)+ethyl alcohol

3h19 – EstE5 SLIPE)+isopropyl alcohol

3g9t, 3g9u - EstE5 (HSLIPE)+p-nitrophenyl butyrate

3g9z - EstE5 (LIPE) +p-nitrophenyl caprylate

2nw6 – BcLip+ S inhibitor

4lip, 5lip, 1r4z, 1r50 – BcLip+ Rc-(Rp,Sp)-1,2-dioctylcarbamoyl-glycero-3-O-phosphonate

1r4z – BsLip+Rc-IPG-phosphonate

1r50 - BsLip+Sc-IPG-phosphonate

1k8q - Lip+phosphonate – dog

1ex9 – Lip+Rc-(Rp,Sp)-1,2-dioctylcarbamoyl-glycero-3-O-phosphonate – Pseudomonas aeruginosa

5tgl – RmLip+N-hexyl-phosphonate

1lpb – Lip (pig)+colipase+C11 alkyl phosphonate

3icw – CaLipB (mutant) +methyl hydrogen R hexylphosphonate

3a70 – PsLip+diethyl phosphate

Lipase conjugated with analogs to its reaction intermediates
1lpn, 1lpo, 1lpp – CrLip+ sulfonates

3rar – CrLip+ phosphonate

1qz3 – EaEst2(mutant) (LIPE)+hexadecanesulfonate

Lipase showing bile-salt binding site
1aql – cBSSL+taurocholate

Lipase with substrate bound at active site
2zyh – AfLip (mutant)+fatty acid – Archaeoglobus fulgidus

2zyi - AfLip+fatty acid+Ca

2zyr - AfLip+fatty acid+Mg

2zys - AfLip+fatty acid+Cl

1gt6 – TlLip+oleic acid - lipid ligand

Lipase conjugated to transition-state analogs showing the binding mode of the enzyme catalysis
1ys1 – BhLip+hexylphosphonic acid (R) 2-methyl-3-phenylpropyl ester

1ys2 – BhLip+hexylphosphonic acid (S) 2-methyl-3-phenylpropyl ester 1hqd – Lip+1-phenoxy-2-acrtoxy butane – Pseudomonas cepacia

Lipase+lipase chaperone
2es4 – Lip+lipase chaperone C-terminal - Burkholderia glumae